Project Title: Combination Nanotherapeutic Strategies to Overcome Tumor Drug Resistance The success of chemotherapeutic treatment of primary ovarian cancer and especially metastatic cells growing in ascitic fluid is limited by the intrinsic and acquired resistance of cancer cells and adverse side effects of chemotherapy. Based on the results of our previous study and literature data, we hypothesize, that the effective treatment of multidrug resistant ovarian tumors is possible only by the simultaneous suppression of cellular resistance and cell death induction by several anticancer agents with different mechanisms of action. Such goals can be achieved if several anticancer agents are simultaneously delivered in one multifunctional system in combination with other active ingredients that perform different specific functions for enhancing cellular uptake and efficiency of the main drug specifically in cancer cells, limiting adverse side effects and preventing the development and/or suppression of the existent drug resistance. In the proposed study, we plan to apply nanotechnology approaches to the development and evaluation of such multifunctional nanotherapeutics. The long-term objective of the proposed research is to verify the hypothesis and develop novel multifunctional Nanocarrier-based Drug Delivery System(s) (NDDS) that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects in healthy organs. A novel internally quaternized and surfaceacetylated poly(amidoamine) dendrimer (QPAMAM-NHAc) will be used as a nanocarrier for NDDS. The NDDS will contain a tumor-specific targeting moiety, two anticancer drugs, and suppressors of pump and nonpump cellular resistance. Paclitaxel, cisplatin/carboplatin and their combination will be evaluated as anticancer drugs - cell death inducers. siRNA targeted to MDR1 and CD44 mRNA will be investigated as suppressors of pump resistance. siRNA targeted to BCL2 mRNA will be studied as a suppressor of nonpump resistance. Established human multidrug resistant ovarian cancer cell lines as well as cells isolated from primary tumor and malignant ascites from patients with advanced multidrug resistant ovarian carcinoma will be used to create ectopic subcutaneous and orthotopic intraperitoneal models in nude mice. Intravenous systemic and intraperitoneal local treatments of experimental cancers will be compared. The results of the proposed work will be used to design novel multifunctional nanotechnology approaches for the treatment of different cancers.